Exendin-4, a glucagon-like peptide-1 analogue accelerates healing of chronic gastric ulcer in diabetic rats

Abstract

BackgroundDiabetes mellitus is an independent risk factor for impaired healing of peptic ulcers, and there are currently no supplementary therapeutics other than the standard antipeptic medicine to improve the ulcer healing in diabetes. This study examined the potential pleiotropic effect of a glucagon-like peptide (Glp)-1 analogue exendin (Ex)-4 on the regeneration of gastric ulcer in streptozotocin-induced diabetic rats.Methods and resultsChronic ulcer was created in rat stomach by submucosal injection of acetic acid and peri-ulcer tissues were analyzed 7 days after operation. Ulcer wound healing was impaired in diabetic rats with suppressed tissue expression of eNOS and enhanced levels of pro-inflammatory reactions. Treatment with intraperitoneal injection of Ex4 (0.5 μg/kg/d) significantly reduced the area of gastric ulcer without changing blood glucose level. Ex-4 restored the expression of pro-angiogenic factors, and attenuated the generation of regional inflammation and superoxide anions. The improvement of ulcer healing was associated with increased expression of MMP-2 and formation of granulation tissue in the peri-ulcer area.ConclusionAdministration of Ex4 may induce pro-angiogenic, anti-inflammatory and anti-oxidative reactions in the peri-ulcer tissue of diabetic rats that eventually enhances tissue granulation and closure of ulcerative wounds. Our results support the potential clinical application of Glp-1 analogues as supplementary hypoglycemic agents in the antipeptic ulcer medication in diabetes.

Gastro-protective actions of Aloe barbadensis Miller mitigate ethanol-induced gastric injury in rats

“…In this study, treatment of gastric ulcer rats with Aloe barbadensis leaf extract led to significant and dose-dependent reduction in gastric tissue MDA level, an indication that the gastroprotective effect of the extract was exerted via suppression of lipid peroxidation in gastric mucosa. Reduced MDA level may in turn inhibit inflammation [22,23].…”

Actions of glucagon‐like peptide‐1 receptor ligands in the gut

“…Similar to the so‐called ‘reparative lineages’ in the gut (Gouyer et al, 2010), the mucous neck cells of the gastric corpus produce mucins (MUC6 and MUC1, Hanby et al, 1999; Gouyer et al, 2010) and growth factors (TFF1, TFF2 and EGF proteins, Gouyer et al, 2010), which are believed to protect the other glandular cells from the acid secreted by neighbouring parietal cells. In accordance, Chen et al recently showed that administration of the GLP‐1 receptor agonist, exendin‐4, accelerated healing of stomach ulcers in diabetic rats (Chen et al, 2017). The strong tdTomato signal in Brunner's glands, which was confirmed by IHC (Baggio et al, 2018; Hepprich et al, 2020; Pyke et al, 2014) and quantitative polymerase chain reaction (qPCR) (Bang‐Berthelsen et al, 2016), is in accordance with earlier findings in humans and monkeys (Orskov & Poulsen, 1991; Qu et al, 2008), and functional studies in mice have shown that liraglutide causes an upregulation of genes in Brunner's glands associated with protection of the intestinal epithelial layer (Glass et al, 2017).…”

“…In further support of these observations, the suppressive effects of intraperitoneal injections of GLP‐1 on food intake and blood glucose levels were attenuated by complete sub‐diaphragmatic vagal de‐afferentation in rats (Hayes et al, 2011), indicating that these systemic effects are mediated in part through activation of GLP‐1 receptors on the vagal afferent nerve terminals. In accordance, intraperitoneal administration of 125 I‐exendin (Billeschou et al, 2021; Billing et al, 2018, 2019; Billings et al, 2018; Brookes et al, 2013; Brubaker, 2018; Bucinskaite et al, 2009; Buckley et al, 2019; Buhl et al, 1988; Canfora et al, 2017; Chen et al, 2017; Christiansen et al, 2018; Christiansen et al, 2019; Daniel et al, 2002; Day et al, 2009; de Heer et al, 2007; Deacon et al, 1995; Drucker & Yusta, 2014; Eissele et al, 1990, 1992; Fehmann et al, 1995; Friis‐Hansen et al, 2001; Gabery et al, 2020; Gasbjerg et al, 2019; Glass et al, 2017; Gouyer et al, 2010; Hanby et al, 1999; Hansen et al, 1999, 2015; Hayes et al, 2011) resulted in labelling of myenteric ganglia of the distal ileum, thus supporting the interpretation of experiments involving intraperitoneal administration of GLP‐1 to reflect interactions with nerve fibres within the myenteric plexus (Hayes et al, 2011).…”

“…The nature of the GLP‐1 receptor‐positive fibres in the intestinal wall is not clear. The strongest antibody staining for GLP‐1 receptors and the greatest accumulation of 125 I‐exendin (Billeschou et al, 2021; Billing et al, 2018, 2019; Billings et al, 2018; Brookes et al, 2013; Brubaker, 2018; Bucinskaite et al, 2009; Buckley et al, 2019; Buhl et al, 1988; Canfora et al, 2017; Chen et al, 2017; Christiansen et al, 2018, 2019; Daniel et al, 2002; Day et al, 2009; de Heer et al, 2007; Deacon et al, 1995; Drucker & Yusta, 2014; Eissele et al, 1990, 1992; Fehmann et al, 1995; Friis‐Hansen et al, 2001; Gabery et al, 2020; Gasbjerg et al, 2019; Glass et al, 2017; Gouyer et al, 2010; Hanby et al, 1999; Hansen et al, 1999, 2015; Hayes et al, 2011) grains were observed in and around myenteric plexuses located in the distal intestine, namely, in the distal ileum and in the proximal and distal large intestine. Myenteric ganglia of the duodenum, jejunum and gastric pylorus also displayed staining for GLP‐1 receptors, whereas the nerve fibres in the gastric corpus and caecum were very weakly stained.…”

Exendin-4 as a Versatile Therapeutic Agent for the Amelioration of Diabetic Changes

“…These features are found to confine the progression of ulcers and accelerate the healing. 33 Anti-cancer effect of Ex-4 T2DM has been shown to predispose the risk of many malignancies, such as colon and breast and other cancer types. 37,38 Previous data demonstrated the anti-cancer properties of Ex-4 on cancer cell types such as breast cancer cells.…”